Immunotherapy-induced isolated ACTH deficiency in cancer therapy

Central adrenal insufficiency (AI) due to isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) has been recently associated with immune checkpoint inhibitor (ICI) therapy. Our aim was to analyze the prevalence, clinical characteristics, and therapeutic outcomes in cancer patients with IAD induced by ICI therapy. A retrospective and multicenter study was performed. From a total of 4,447 cancer patients treated with ICI antibodies, 37 (0.8%) [23 men (62.2%), mean age 64.7 ± 8.3 years (range 46-79 yr)] were diagnosed with IAD. The tumor most frequently related to IAD was lung cancer (n=20, 54.1%), followed by melanoma (n=8, 21.6%). The most commonly ICI antibody inhibitor reported was nivolumab (n=18, 48.6%), pembrolizumab (n=16, 43.2%) and ipilimumab (n=8, 21.6%). About half of the patients (n=19, 51.4%) had other immune-related adverse events, mainly endocrine adverse effects (n=10, 27.0%). IAD was diagnosed at a median time of 7.0 months (IQR, 5-12) after starting immunotherapy. The main reported symptom at presentation was fatigue (97.3%), followed by anorexia (81.8%) and general malaise (81.1%). Mean follow-up time since IAD diagnosis was 15.2 ± 12.5 months (range 0.3-55 months). At last visit all patients continued with hormonal deficiency of ACTH. Median overall survival since IAD diagnosis was 6.0 months. In conclusion, IAD is a rare but a well-established complication associated with ICI therapy in cancer patients. It develops around 7 months after starting treatment, mainly anti-PD1 antibodies. Recovery of the corticotropic axis function should not be expected.

Missplicing due to a synonymous, T96= exonic substitution in the T-box transcription factor TBX19 resulting in isolated ACTH deficiency

Summary Congenital isolated ACTH deficiency (IAD) is a rare condition characterised by low plasma ACTH and serum cortisol with normal production of other pituitary hormones. TBX19 (also known as TPIT) is a T-box pituitary restricted transcription factor important for POMC gene transcription and terminal differentiation of POMC-expressing cells. TBX19 gene mutations have been shown to cause neonatal-onset congenital IAD. We report a neonate of Romanian origin, who presented at 15 h of life with respiratory arrest and hypoglycaemia which recurred over the following 2 weeks. Biochemical investigations revealed IAD, with undetectable serum cortisol (cortisol < 1 μg/dL; normal range (NR): 7.8–26.2) and plasma ACTH levels within the normal range (22.1 pg/mL; NR: 4.7–48.8). He responded to hydrocortisone treatment. Patient DNA was analysed by a HaloPlex next-generation sequencing array targeting genes for adrenal insufficiency. A novel homozygous synonymous mutation p.Thr96= (Chr1:168260482; c.288G>A; rs376493164; allele frequency 1 × 10−5, no homozygous) was found in exon 2 of the TBX19 gene. The effect of this was assessed by an in vitro splicing assay, which revealed aberrant splicing of exon 2 giving rise to a mutant mRNA transcript whereas the WT vector spliced exon 2 normally. This was identified as the likely cause of IAD in the patient. The predicted protein product would be non-functional in keeping with the complete loss of cortisol production and early presentation in the patient. Learning points Synonymous variants (a nucleotide change that does not alter protein sequence) usually thought to be benign may still have detrimental effects on RNA and protein function causing disease. Hence, they should not be ignored, especially if very rare in public databases. In vitro splicing assays can be employed to characterise the consequence of intronic and exonic nucleotide gene changes that may alter splicing. Establishing a diagnosis due to a TBX19 mutation is important as it defines a condition of isolated ACTH deficiency not associated with additional pituitary deficiencies.

Abdominal pain as an initial symptom of isolated ACTH deficiency induced by nivolumab in a patient with malignant mesothelioma

Used for a wide range of cancers, nivolumab has been reported to cause immune-related adverse events, including isolated adrenocorticotropic hormone deficiency (IAD). We report an 81-year-old woman with malignant mesothelioma who presented with abdominal pain after eight courses of nivolumab therapy, leading to the diagnosis of nivolumab-induced IAD. We should consider adrenal insufficiency (AI) when a patient on nivolumab complains of abdominal pain and has no other explanatory findings. Infusion-resistant hypotension and hyponatraemia can further suggest AI.

HYPOGLYCEMIA AS INITIAL PRESENTATION IN PATIENT WITH ISOLATED ACTH DEFICIENCY

Objective: Isolated adrenocorticotropic hormone (ACTH) deficiency is characterized by loss of adrenocorticotropic hormone, resulting in adrenal insufficiency, which can lead to life threatening severe hypoglycemia. We report a case of isolated ACTH deficiency with emphases on presentation, common etiologies, diagnosis, and management. Methods: The clinical course in addition to laboratory and imaging results are presented. These include cortisol level, ACTH, other pituitary hormones, insulin tolerance test, pituitary antibodies, and pituitary magnetic resonance imaging. Results: A 19-year-old male was brought by ambulance to the emergency department with loss of consciousness and a random blood sugar of 30 mg/dL. Our patient had a barely detectable level of plasma ACTH repeatedly and cortisol <1 μg/dL. There was no involvement of other pituitary hormones. Steroid replacement therapy led to resolution of all symptoms and prevented further episodes of hypoglycemia. Conclusion: Isolated ACTH deficiency is a rare condition that is challenging to diagnose and can lead to serious life-threatening problems if unrecognized. Proper management can be achieved with appropriate hydrocortisone supplementation to mimic the normal secretion under both normal conditions and during a state of stress.

Clinical features and aetiology of newly diagnosed adrenal insufficiency: A single-centre retrospective cross-sectional study in Japan.

Background: Central adrenal insufficiency (AI) has been reported to be twice as common as primary AI outside Japan. The most common causes of central AI are drugs and pituitary tumours. However, given the significant differences in the incidence rates of Addison’s disease and isolated ACTH deficiency between Japan and other countries, the most common causes of AI in Japan may differ from those in other countries. Furthermore, few studies have focused on the clinical features of newly diagnosed central AI.Methods: A retrospective single-centre observational study using electronic medical records from April 2012 to December 2019 was conducted. The main outcome was the proportion of cases of central AI among all cases of newly diagnosed AI. We also investigated the clinical features and common causes of central AI. Only patients with AI confirmed with hormone tests were included. Patients with AI who were asymptomatic or diagnosed clinically without hormone test confirmation were excluded. Based on hormone tests and the clinical diagnosis, AI was classified into primary and central AI.Results: A total of 34 patients were eligible. The mean patient age was 76.3 years, 11 (32.4%) were women, and 11 (32.4%) were former or current users of glucocorticoids for non-endocrine diseases. Of the 34 patients with newly diagnosed AI, all (100.0%) had central AI. The most common cause of central AI was glucocorticoids (n = 11, 32.4%), followed by central hypoadrenalism of unknown causes (n = 9, 26.5%), idiopathic isolated ACTH deficiency (n = 6, 17.7%), and pituitary tumours (n = 5, 14.7%). For the 34 patients with central AI, the mean time to receive a correct diagnosis from the onset was 6.2 months. The most common symptoms at diagnosis were anorexia (n = 26, 76.5%), fatigue (n = 23, 67.6%), asthenia (n = 22, 64.7%) and nausea or vomiting (n = 19, 55.9%).Conclusions: Primary AI is rare in Japan. The most common cause of newly diagnosed central AI is glucocorticoid use. Pituitary tumours may be a less common cause of central AI in Japan than in other countries.